Low density microspheres and their use as contrast agents for computed tomography

ABSTRACT

Substantially homogeneous aqueous suspensions of low density microspheres are presented as contrast media for imaging the gastrointestinal tract and other body cavities using computed tomography. In one embodiment, the low density microspheres are gas-filled. With computed tomography, the contrast media serve to change the relative density of certain areas within the gastrointestinal tract and other body cavities, and improve the overall diagnostic efficacy of this imaging method.

RELATED APPLICATIONS

This application is a divisional of U.S. Ser. No. 07/980,594, filed Jan.19, 1993, U.S. Pat. No. 5,281,408 which in turn is a divisional of U.S.Ser. No. 07/680,984, filed Apr. 5, 1991, now U.S. Pat. No. 5,205,290.

BACKGROUND OF THE INVENTION

Computed tomography (CT) is a widespread diagnostic imaging method whichmeasures, in its imaging process, the radiodensity (electron density) ofmatter. This radiodensity is depicted using CT in terms of HounsefieldUnits (HU). Hounsefiled Units, named after the inventor of the first CTscanner, reflect the relative absorption of CT X-rays by matter, theabsorption being directly proportional to the electron density of thatmatter. Water, for example, has a value of 0 HU, air a value of -1000HU, and dense cortical bone a value of +1000 HU. Because of thesimilarity in density of various tissues in the body, however, contrastagents have been sought to change the relative density of differenttissues, and improve the overall diagnostic efficacy of this imagingmethod.

In the search for contrast agents for CT, researchers have generallysought to develop agents that will increase electron density in certainareas of a region of the body (positive contrast agents). Barium andiodine compounds, for example, have been developed for this purpose. Forthe gastrointestinal tract, barium sulfate is used extensively toincrease the radiodensity of the bowel lumen on CT scans. Iodinatedwater soluble contrast media are also used to increase density withinthe gastrointestinal tract, but are not used as commonly as the bariumcompounds, primarily because the iodine preparations are more expensivethan barium and prove less effective in increasing radiodensity withinthis region of the body.

Despite their widespread use, however, barium and iodine compounds aresuboptimally effective as gastrointestinal contrast agents for CT. Forexample, if the concentration is too low, there is little contrast.Conversely, if the concentration is too high, then these radiodensecontrast agents cause beam hardening artifacts which are seen as streakson the CT images. It is also difficult to visualize the bowel mucosawith either the barium or iodine contrast agents.

In an attempt to improve upon the efficacy of contrast agents for thegastrointestinal tract, lipid emulsions that are capable of decreasingelectron density (negative contrast agents) have been developed. Becauselipids have a lower electron density than water, lipids provide anegative density on CT (a negative HU value). While these lipidemulsions appear to be more effective than the barium and iodine agentsat improving visualization of the mucosa of the bowel, these contrastagents have limitations. First, there is a limitation to theconcentration of lipid which a patient can tolerably drink, which puts alimit on the change in density (or HU) which the lipid based CT contrastagent can provide. Lipid emulsions are also frequently expensive.Furthermore, these lipid formulations are generally perishable, whichprovides for packaging and storage problems.

New and/or better contrast agents for computed tomography imaging areneeded. The present invention is directed toward this important end.

SUMMARY OF THE INVENTION

The present invention is directed to computed tomography imaging, andmore particularly to the use of a contrast medium comprising asubstantially homogeneous aqueous suspension of low density microspheresto image the gastrointestinal region and other body cavities of apatient. In one embodiment, the low density microspheres are gas-filled.

Specifically, the present invention pertains to methods of providing animage of the gastrointestinal region or other body cavities of a patientcomprising (i) administering to the patient the aforementioned contrastmedium, and (ii) scanning the patient using computed tomography imagingto obtain visible images of the gastrointestinal region or other bodycavities.

The present invention is further directed to methods for diagnosing thepresence of diseased tissue in the gastrointestinal region or other bodycavities of a patient comprising (i) administering to the patient theaforementioned contrast medium, and (ii) scanning the patient usingcomputed tomography imaging to obtain visible images of any diseasedtissue in the patient.

The present invention also provides diagnostic kits for computedtomography imaging of the gastrointestinal region or other body cavitieswhich include the subject contrast medium.

DETAILED DESCRIPTION OF THE INVENTION

A wide variety of different low density microspheres may be utilized inthe present invention. Preferably, the microspheres (which are smallspheres having a central void or cavity), are composed of biocompatiblesynthetic polymers or copolymers prepared from monomers such as acrylicacid, methacrylic acid, ethyleneimine, crotonic acid, acrylamide, ethylacrylate, methyl methacrylate, 2-hydroxyethyl methacrylate (HEMA),lactic acid, glycolic acid, ε-caprolactone, acrolein, cyanoacrylate,bisphenol A, epichlorhydrin, hydroxyalkylacrylates, siloxane,dimethylsiloxane, ethylene oxide, ethylene glycol,hydroxyalkyl-methacrylates, N-substituted acrylamides, N-substitutedmethacrylamides, N-vinyl-2-pyrrolidone, 2,4-pentadiene-1-ol, vinylacetate, acrylonitrile, styrene, p-amino-styrene, p-amino-benzylstyrene,sodium styrene sulfonate, sodium 2-sulfoxyethylmethacrylate, vinylpyridine, aminoethyl methacrylates, 2-methacryloyloxy-trimethylammoniumchloride, and polyvinylidene, as well polyfunctional crosslinkingmonomers such as N,N'-methylenebisacrylamide, ethylene glycoldimethacrylates, 2,2'-(p-phenylenedioxy)diethyl dimethacrylate,divinylbenzene, triallylamine and methylenebis-(4-phenyl-isocyanate),including combinations thereof. Preferable polymers include polyacrylicacid, polyethyleneimine, polymethacrylic acid, polymethylmethacrylate,polysiloxane, polydimethylsiloxane, polylactic acid,poly(ε-caprolactone), epoxy resin, poly(ethylene oxide), poly(ethyleneglycol), and polyamide (nylon). Preferable copolymers include thefollowing: polyvinylidene-polyacrylonitrile,polyvinylidene-polyacrylonitrile-polymethylmethacrylate, andpolystyrene-polyacrylonitrile. A most preferred copolymer ispolyvinylidene-polyacrylonitrile. The term biocompatible, as used hereinin conjunction with the terms monomer or polymer, is employed in itsconventional sense, that is, to denote polymers that do notsubstantially interact with the tissues, fluids and other components ofthe body in a adverse fashion in the particular application of interest,such as the aforementioned monomers and polymers. Other suitablebiocompatible monomers and polymers will be readily apparent to thoseskilled in the art, once armed with the present disclosure.

The microspheres of the present invention are low density. By lowdensity, it is meant that the microspheres of the invention have aninternal void (cavity) volume which is at least about 75% of the totalvolume of the microsphere. Preferably, the microspheres have a voidvolume of at least about 80%, more preferably at least about 85%, evenmore preferably at least about 90%, of the total volume of themicrospheres.

The microspheres may be of varying size, provided they are low density.Suitable size microspheres include those ranging from between about 1and about 1000 microns in outside diameter, preferably between about 5and about 70 microns in outside diameter. Most preferably, themicrospheres are about 50 microns in outside diameter.

The microspheres of the invention may be prepared by various processes,as will be readily apparent to those skilled in the art, once armed withthe present disclosure, such as by interfacial polymerization, phaseseparation and coacervation, multiorifice centrifugal preparation, andsolvent evaporation. Suitable procedures which may be employed ormodified in accordance with the present invention include thoseprocedures disclosed in Garner et al., U.S. Pat. No. 4,179,546, Garner,U.S. Pat. No. 3,945,956, Cohrs et al., U.S. Pat. No. 4,108,806, JapanKokai Tokkyo Koho 62 286534, Britich Patent No. 1,044,680, Kenaga etal., U.S. Pat. No. 3,293,114, Morehouse et al., U.S. Pat. No. 3,401,475,Walters, U.S. Pat. No. 3,479,811, Walters et al., U.S. Pat. No.3,488,714, Morehouse et al., U.S. Pat. No. 3,615,972, Baker et al., U.S.Pat. No. 4,549,892, Sands et al., U.S. Pat. No. 4,540,629, Sands et al.,U.S. Pat. No. 4,421,562, Sands, U.S. Pat. No. 4,420,442, Mathiowitz etal., U.S. Pat. No. 4,898,734, Lencki et al., U.S. Pat. No. 4,822,534,Herbig et al., U.S. Pat. No. 3,732,172, Himmel et al., U.S. Pat. No.3,594,326, Sommerville et al., U.S. Pat. No. 3,015,128, Deasy,Microencapsulation and Related Drug Processes, Vol. 20, Chs. 9 and 10,pp. 195-240 (Marcel Dekker, Inc., N.Y., 1984), Chang et al., Canadian J.of Physiology and Pharmacology, Vol 44, pp. 115-129 (1966), and Chang,Science, Vol. 146, pp. 524-525 (1964), the disclosures of each of whichare incorporated herein by reference in their entirety.

In accordance with the preferable synthesis protocol, the microspheresare prepared using a heat expansion process such as is described inGarner et al., U.S. Pat. No. 4,179,546, Garner, U.S. Pat. No. 3,945,956,Cohrs et al., U.S. Pat. No. 4,108,806, British Patent No. 1,044,680, andJapan Kokai Tokkyo Koho 62 286534. In general terms, the heat expansionprocess is carried out by preparing microspheres of an expandablepolymer or copolymer which contain in their void (cavity) a volatileliquid. The microsphere is then heated, plasticising the microsphere andvolatilizing the gas, causing the microsphere to expand to up to aboutseveral times its original size. When the heat is removed, thethermoplastic polymer retains at least some of its expanded shape.Microspheres produced by this process tend to be of particularly lowdensity, and are thus preferred. The foregoing described process is wellknown in the art, and is referred to herein as the heat expansionprocess for preparing low density microspheres.

Polymers useful in the heat expansion process will be readily apparentto those skilled in the art and include thermoplastic polymers orcopolymers, including polymers or copolymers of many of the monomersdescribed above. Preferable of the polymers and copolymers describedabove include the following copolymers:polyvinylidene-polyacrylonitrile,polyvinylidene-polyacrylonitrile-polymethylmethacrylate, andpolystyrene-polyacrylonitrile. A most preferred copolymer ispolyvinylidene-polyacrylonitrile.

Volatile liquids useful in the heat expansion process will also be wellknown to those skilled in the art and include: aliphatic hydrocarbonssuch as ethane, ethylene, propane, propene, butane, isobutane,neopentane, acetylene, hexane, heptane; chlorofluorocarbons such as CCl₃F, CCl₂ F₂, CClF₃, CClF₂ -CCl₂ F₂, ##STR1## tetraalkyl silanes such astetramethyl silane, trimethylethyl silane, trimethylisopropyl silane,and trimethyl n-propyl silane; as well as perfluorocarbons such as thosehaving between 1 an about 9 carbon atoms and between about 4 and about20 fluorine atoms, especially C₄ F₁₀. In general, it is important thatthe volatile liquid not be a solvent for the microsphere polymer orcopolymer. The volatile liquid should also have a boiling point that isbelow the softening point of the microsphere polymer or co-polymer.Boiling points of various volatile liquids and softening points ofvarious polymers and copolymers will be readily ascertainable to oneskilled in the art, and suitable combinations of polymers or copolymersand volatile liquids will be easily apparent to the skilled artisan. Byway of guidance, and as one skilled in the art would recognize,generally as the length of the carbon chain of the volatile liquidincreases, the boiling point of that liquid increases. Also, by mildlypreheating the microspheres in water in the presence of hydrogenperoxide prior to definitive heating and expansion may pre-soften themicrosphere to allow expansion to occur more readily.

For example, to produce microspheres of the present invention,vinylidene and acrylonitrile may be copolymerized in a medium ofisobutane liquid using one or more of the foregoing modified orunmodified literature procedures, such that isobutane becomes entrappedwithin the microspheres. When such microspheres are then heated tobetween about 80° C. and about 120° C., the isobutane gas expands, whichi turn expands the microspheres. After heat is removed, the expandedpolyvinylidene and acrylonitrile copolymer microspheres remainsubstantially fixed in their expanded position. The resulting lowdensity microspheres are extremely stable both dry and suspended in anaqueous media. Isobutane is utilized merely as an illustrative liquid,with the understanding that other liquids which undergo liquid/gastransitions at temperatures useful for the synthesis of thesemicrospheres and formation of the very low density microspheres uponheating can be substituted for isobutane. Similarly, monomers other thanvinylidene and acrylonitrile may be employed in preparing themicrosphere.

Most preferably, the low density microspheres employed are thosecommercially available for Expancel, Nobel Industries, Sundsvall,Sweden, such as the EXPANCEL 551 DE™ microspheres. The EXPANCEL 551 DE™microspheres are composed of a copolymer of vinylidene and acrylonitrilewhich have encapsulated therein isobutane liquid. Such microspheres aresold as a dry composition and are approximately 50 microns in size. TheEXPANCEL 551 DE™ microspheres have a specific gravity of only 0.02 to0.05, which is between one-fiftieth and one-twentieth the density ofwater.

In one embodiment, the microspheres of the present invention aregas-filled. By gas-filled, it is meant that at least part of the voidvolume inside the microspheres is occupied by the gas. Preferably,substantially all of the void volume inside the microspheres is occupiedby the gas. The gas may be any type of gas, such as, for example, carbondioxide, oxygen, nitrogen, xenon, argon, neon, helium and air.Preferably, the gas is carbon dioxide, oxygen, nitrogen, xenon, argon,neon and helium. Most preferably, the gas is inert, that is, a gas thatis substantially resistance to chemical or physical action. Thegas-filled low density microspheres may be synthesized under pressuresuch that gases are solubilized in the liquid employed in microspheresynthesis. When the pressure is removed, the gas comes out of solutionto fill the microsphere void. Such microspheres can further be subjectedto a heat expansion process, as described above.

For example, to produce the gas-filled microspheres of the invention,one may copolymerize vinylidene and acrylonitrile using one or more ofthe foregoing procedures, such as phase separation/coacervationtechniques in a pressurized and/or low temperature environment (e.g., atabout 300 psi, and/or at about 0° C.) with a high concentration ofdissolved gas (e.g., dissolved nitrogen) in solution, to form a largemicrosphere containing the dissolved gas. When the pressure is removedand/or the temperature raised, the gas bubbles come out of solution,forming as filled microspheres. Such microspheres can further besubjected to a heat expansion process, as described above.

It is preferable that the microspheres be relatively stable in thegastrointestinal tract or other body cavities during the length of timenecessary for completing and imaging examination. Low densitymicrospheres prepared from the aforementioned monomer and polymercompositions will provide such stable microspheres.

In order for these microspheres to serve as effective CT contrastagents, it is necessary for the microspheres to be mixed in solution ina substantially homogeneous suspension. This can be accomplished byusing thickening and suspending agents. A wide variety of thickening andsuspending agents may be used to a prepare the substantially homogeneoussuspensions of the microspheres. Suitable thickening and suspendingagents, for example, include any and all biocompatible agents known inthe art to act as thickening and suspending agents. Particularly usefulare the natural thickening and suspending agents aliginates, xanthangum, guar, pectin, tragacanth, bassorin, karaya, gum arabic, casein,gelatin, cellulose, sodium carboxymethylcellulose, methylcellulose,methylhydroxycellulose, bentonite, colloidal silicic acid, andcarrageenin, and the synthetic thickening and suspending agentspolyethylene glycol, polypropylene glycol, and polyvinylpyrrolidone. Asthose skilled in the art would recognize, once armed with the presentdisclosure, the suspending agents may be formulated, if desired, to beeither less dense than water or of neutral density, so as to notsubtract from the density lowering capabilities of the microspheres. Forexample, a cellulose suspension may have a somewhat lower density thanwater, e.g., a 2 weight % cellulose solution with 0.25 weight % xanthangum has a density of 0.95. The thickening and suspending agents may beemployed in varying amounts, as those skilled in the art wouldrecognize, but preferably are employed in amounts of about 0.25 to about10 weight % preferably about 0.5 to about 5 weight % of the contrastmedium.

The substantially homogeneous, aqueous suspension of low densitymicrospheres of the invention are useful as CT contrast agents. Theseagents are capable of producing negative contrast in thegastrointestinal tract or in other body cavities, providing effectivecontrast enhancement and improved visualization in these areas of thebody. Specifically, the present invention is directed to a method ofproviding an image of or detecting diseased tissue in thegastrointestinal region and other body cavities of a patient, the methodcomparing administering to the patient a contrast medium comprising asubstantially homogeneous aqueous solution of low density microspheres,and scanning the patient using computed tomography imaging to obtainvisible images of the gastrointestinal region or other body cavities orof diseased tissue in these areas of the body.

The phrase gastrointestinal region or gastrointestinal tract, as usedherein, includes the region of a patient defined by the esophagus,stomach, small and large intestines, and rectum. The phrase other bodycavities, as used herein, includes any region of the patient, other thanthe gastrointestinal region, having an open passage, either directly orindirectly, to the external environment, such regions including thesinus tracts, the fallopian tubes, the bladder, etc. The patient can beany type of mammal, but most preferably is a human.

As one skilled in the art would recognize, administration of thecontrast medium to the patient may be carried out in various fashions,such as orally, rectally, or by injection. When the region to be scannedis the gastrointestinal region, administration of the contrast medium ofthe invention is preferably carried out orally or rectally. When otherbody cavities such as the fallopian tubes or sinus tracts are to bescanned, administration is preferably by injection. As would also berecognized by one skilled in the art, wide variations in the amounts ofthe gas filled microspheres can be employed in the methods and kits ofthe invention, with the precise amounts varying depending upon suchfactors as the mode of administration (e.g., oral, rectal, byinjection), and the specific body cavity and portion thereof for whichan image is sought (e.g., the stomach of the gastrointestinal tract).Typically, dosage is initiated at lower levels and increased until thedesired contacts enhancement is achieved.

For CT imaging, it is generally desirable to decrease the density of thelumen of the gastrointestinal tract or other body cavities to at leastabout -30 HU, the maximum decrease being limited by the practical amountof the microspheres which may be suspended in the aqueous media andingested by the patient. In general, a decrease in HU to between about-30 HU and about -150 HU is sufficient to mark the inside of the bowelor other body cavity. By way of general guidance, and as a rough rule ofthumb, to decrease the density of the microsphere aqueous suspension toabout -150 HU, the microspheres must occupy about 15% of the totalvolume of the aqueous suspension. To achieve a density of about -50 HU,the microspheres must occupy about 5% of the total volume of thesolution. The volume of contrast agent administered to the patient istypically between about 50 to about 1000 cc. Using the EXPANCEL 551 DE™microspheres as a model, it has been found that about 0.6 grams of thedry 50 micron spheres in 100 cc of aqueous suspension is sufficient todecrease the density of the suspension to nearly -150 HU.

It should be noted that smaller microspheres are generally more stablein suspension, but usually have higher specific gravity than largermicrospheres. Therefore, for CT, the size and particular microspheres,as well as the suspending media (thickening and suspending agents)should selected to minimize specific gravity, while maximizing thestability of the suspension.

The contrast medium utilized of the present invention may also beemployed with other conventional additives suitable for use in theapplications contemplated for the subject invention.

Where gastrointestinal applications are concerned, such additivesinclude conventional biocompatible anti-gas agents, osmolality raisingagents, gastrointestinal transit agents (the later agents serving todecrease the gastrointestinal transit time and increase the rate ofgastrointestinal emptying) and, in some instances, gas-forming agents.

As used herein the term anti-gas agent is a compound that serves tominimize or decrease gas formation, dispersion and/or adsorption. Anumber of such agents are available, including antacids, antiflatulents,antifoaming agents, and surfactants. Such antacids and antiflatulentsinclude, for example, activated charcoal, aluminum carbonate, aluminumhydroxide, aluminum phosphate, calcium carbonate, dihydroxyaluminumsodium carbonate, magaldrate magnesium oxide, magnesium trisilicate,dimethicone, sodium carbonate, loperamide hydrochloride, diphenoxylate,hydrochloride with atropine sulfate, Kaopectate™ (kaolin) and bismuthsalts. Suitable antifoaming agents useful as anti-gas agents includedimethicone, protected dimethicone, siloxyalkylene polymers, siloxaneglycol polymers. polyoxypropylene-polyoxyethylene copolymers,polyoxyalkylene amines and imines, branched polyamines, mixedoxyalkylated alcohols, finely divided silica either alone or mixed withdimethyl polysiloxane, sucroglycamides (celynols), polyoxylalkylatednatural oils, halogenated silicon-containing cyclic acetals, laurylsulfates, 2-lactylic acid esters of unicarboxylic acids, triglycerideoils. Particles of polyvinyl chloride or silica may also function asanti-foaming agents in the subject invention. Suitable surfactantsinclude perfluorocarbon surfactants, such as, for example, DuPont Zonyl™perfluoroalkyl surfactants known as Zonyl™ RP or Zonyl™ NF, availablefrom DuPont, Chemicals and Pigments Division Jackson Laboratory,Deepwater N.J. 08023. Of course, as those skilled in the art willrecoginze, any anti-gas agents employed must be suitable for use withinthe particular biological system of the patient in which it is to beused. The concentration of such anti-gas agents may vary widely, asdesired, as will be readily apparent to those skilled in the art.Typically, however, such agents are employed in concentrations ofbetween about 20 and about 2000 ppm, most preferably in concentrationsbetween about 50 and about 1000 ppm.

Suitable osmolality raising agents include polyols and sugars, forexample, mannitol, sorbitol, arabitol, xylitol, glucose, sucrose,fructose, dextrose, and saccharine, with mannitol and sorbitol beingmost preferred. The concentration of such osmolality raising agents mayvary, as desired, however, generally a range of about 5 to about 70 g/l,preferably about 30 to about 50 g/l of the contrast medium. Suchcompounds may also serve as sweeteners for the ultimate formulation, ifdesired.

Gastrointestinal transit agents include algin, as well as many of thecompounds listed above as thickening and suspending agents, with alginbeing most preferred. The amount of such agents will, of course, vary asthose skilled in the art will recognize, but generally will be employedin an amount of between about 5 and about 40 mmol/l.

In some applications, it maybe helpful to incorporate gas-forming agentsinto the contrast medium. Gas-forming agents include sodium bicarbonate,calcium carbonate, aminomalonate, and the like, which will form gas, forexample, upon introduction into the gastrointestinal tract. Suchgas-forming agents will serve to distend the gastrointestinal tract andcreate a form of "double contrast" between the gas and the low densitymicrospheres.

Kits useful for computed tomography imaging of the gastrointestinalregion or other body cavities in accordance with the present inventioncomprise low density microspheres, and a thickening or suspending agent,in addition to conventional computed tomography imaging kit components.Such conventional computed tomography kit components will be readilyapparent to those skilled in the art, once armed with the presentdisclosure.

Where imaging of the gastrointestinal region is contemplated, suchcomputed tomography kit components may include, for example, anti-gasagents, osmolality raising agents, gastrointestinal transit agents and,in some instances, gas-forming agents.

The computed tomography imaging principles and techniques which areemployed are conventional and are described, for example in ComputedBody Tomography, Lee J. K. T., Sagel, S. S., and Stanly, R. J., eds.,Ch. 1, pp. 1-7 (Raven Press, N.Y. 1933). Any of the various types ofcomputed tomography imaging devices can be used in the practice of theinvention, the particular type or model of the device not being criticalto the method of the invention.

The present invention is further described in the following Examples.Examples 1-7 are prophetic examples based at least in part on theteachings of Garner, U.S. Pat. No. 3,945,956, and describe thepreparation of microspheres by a heat expansion process. Examples 8-9are actual examples that describe the preparation of contrast media ofthe invention. The following Examples are not to be construed aslimiting the scope of the appended Claims.

EXAMPLES Example 1

A vessel is filled with 50 parts by weight of deionized water and 6parts by weight of a 25 percent by with aqueous colloidal silicadispersion. A mixture of 0.3 parts by weight of a 10 weight percentsolution of diethylamine-adipic acid copolymer is added to the above. Acondensation reaction occurs creating a mixture having a viscosity ofabout 95 centipoise at a temperature of about 27° C. Potassiumdichromate (0.05 parts by weight) is added to the aqueous phase as awater phase polymerization inhibitor. Sodium chloride (1 part by weight)is also present in the water phase; hydrochloric acid is used to adjustthe pH of the aqueous phase to 4.0. Styrene (15 parts by weight),acrylonitrile (10 parts by weight), a mixture of diethylbenzene anddivinylbenzene (0.21 parts by weight comprising a 55:45 percent mixtureof each respectively), 6.25 parts by weight of isobutane and 0.07 partsby weight of secondary butyl peroxydicarbonate. The oil phase is addedto the water phase with violent agitation created by a shearing bladerotating at 10,000 RPM employing a mixing blender. After the materialhas reacted for about 30 minutes, the mixture is poured into a citratebottle and capped. The material is maintained at about 50° C. in thecitrate bath for about 24 hours and agitated throughout this time. Atthe end of 24 hours, the reaction bottle is cooled and the material isremoved, washed and dried. A portion of the microspheres are set asideand the remainder are heated in an air oven for a period of about 30minutes at about 150° C. A sample of the dry unexpanded and dry expandedmicrospheres are then studied by a Coulter Counter. The dry unexpandedmicrospheres have a size of about 2 to 12 microns. About half of themicrospheres exposed to the heating process show expansion.

Example 2

The procedures of Example 1 are substantially repeated with theexception that 1 part by weight of methanol is added to the reactionmixture. The dry unexpanded and dry heat expanded microspheres are thenstudied by Coulter Counter. The dry unexpanded microspheres measureabout 8 to 10 microns in size. Essentially all the microspheres exposedto heat expand.

Example 3

The procedures of Example 2 are substantially repeated except that aftersynthesis of the microspheres, a slurry of the microspheres is added toan aqueous solution containing 35 weight percent hydrogen peroxide. Thisslurry is hated to a temperature of about 50° C. for about 3.5 hours andsubsequently cooled and air-dried. A portion of the microspheres is thenadded to water and heated to a temperature of about 75° C. with vigorousstirring for about 30 seconds. Study with Coulter Counter shows thatpretreatment with hydrogen peroxide enables a lower temperature andbriefer period of heating to be used for definitive heating andexpansion.

Example 4

The procedures of Example 1 are substantially repeated with theexception that 5 parts by weight of ethanol are included in the reactionmixture forming the microspheres. Coulter Counter shows that the dryunexpanded particles have diameters of about 24 to 28 microns. Whenheated, essentially all of the microspheres expand.

Example 5

The procedures of Example 1 are substantially repeated with theexception that in place of methanol, 1 part by weight of normal butanolis used. The diameter of the dry unexpanded microspheres is about 10 to12 microns and on heating, essentially all of the microspheres expand.

Example 6

The procedures of Example 1 are substantially repeated with theexception that the volatile liquid isobutane is replaced withperfluorocarbon liquid (C₄ F₁₀). The remainder of the process issimilar. The resulting microspheres are filled with perfluorocarbonliquid rather than isobutane.

Example 7

The procedures of Example 1 are substantially repeated with theexception that the reaction is conducted in a pressurized vesselenabling pressurization with gas and simultaneous agitation (agitationaccomplished with either sonication or shearing blades within thedevice). As the microspheres are formed within the device, the vessel ispressurized to about 300 psi with nitrogen gas. The vessel is thendepressurized, allowing the gas to come out of solution. Themicrospheres are then subjected to heat as substantially described inExample 1.

Example 8

A suspension of 2% of 22 micron fiber length cellulose in 0.25% xanthangum in water was prepared. Scans by CT showed a CT density of about -45HU for the cellulose suspension. EXPANCEL 551 DE™polyvinylidene-polyacrylonitrile microspheres, 50 microns in size, werethen suspended in the aqueous cellulose suspension at a concentration of0.4 grams of microspheres per 100 ml of cellulose suspension usingvigorous shaking. The resulting suspension remained substantiallyhomogeneous for about 10 minutes. The suspension was again shakenvigorously to render is substantially homogeneous and scannedimmediately by CT. The resulting CT density as measured by the scannerwas about -96 HU.

Example 9

A suspension of 1% algin was prepared. EXPANCEL 551 DE™ microsphereswere added to the algin suspension in an amount of about 0.2 grams ofmicrospheres per deciliter of algin suspension, using vigorous shaking,to form a substantially homogeneous suspension. The resulting suspensionwas found to have much greater stability than the cellulose/microspheresuspension of Example 1. The algin/microsphere suspension was thenscanned by CT, with the density as measured by the scanner being about-40 HU.

Various modifications of the invention in addition to those shown anddescribed herein will be apparent to those skilled in the art from theforegoing description. Such modifications are also intended to fallwithin the scope of the appended Claims.

What is claimed is:
 1. A contrast medium for computed tomography imagingof the gastrointestinal region or other body cavities comprising asubstantially homogeneous aqueous suspension of low density gas-filledmicrospheres having an internal void volume of at least about 75% of thetotal volume of said microsphere.
 2. A contrast medium according toclaim 1 wherein said microspheres comprise synthetic polymers orcopolymers prepared from the group of monomers consisting of acrylicacid, methacrylic acid, ethyleneimine, crotonic acid, acrylamide, ethylacrylate, methyl methacrylate, 2-hydroxyethyl methacrylate, lactic acid,glycolic acid, ε-caprolactone, acrolein, cyanoacrylate, bisphenol A,epichlorhydrin, hydroxyalkylacrylates, siloxane, dimethylsiloxane,ethylene oxide, ethylene glycol, hydroxyalkyl-methacrylates,N-substituted acrylamides, N-substituted methacrylamides,N-vinyl-2-pyrrolidone, 2,4-pentadiene-1-ol, vinyl acetate,acrylonitrile, styrene, p-amino-styrene, p-amino-benzyl-styrene, sodiumstyrene sulfonate, sodium 2-sulfoxyethyl methacrylate, vinyl pyridine,aminoethyl methacrylates, 2-methacryloyloxy-trimethylammonium chloride,N,N'-methylenebisacrylamide, ethylene glycol dimethacrylates,2,2'-(p-phenylenedioxy)-diethyl dimethacrylate, divinylbenzene,triallylamine, and methylenebis-(4-phenyl-isocyanate.
 3. A contrastmedium according to claim 2 wherein said microspheres comprise syntheticpolymers or copolymers prepared from the group of monomers consisting ofacrylic acid, methacrylic acid, ethyleneimine, crotonic acid,acrylamide, ethyl acrylate, methyl methacrylate, 2-hydroxyethylmethacrylate, lactic acid, glycolic acid, ε-caprolactone, acroleincyanoacrylate, bisphenol A, epichlorhydrin, hydroxyalkylacrylates,siloxane, dimethylsiloxane, ethylene oxide, ethylene glycol,hydroxyalkyl-methacrylates, N-substituted acrylamides, N-substitutedmethacrylamides, N-vinyl-2-pyrrolidone, 2,4-pentadiene-1-ol, vinylacetate, acrylonitrile, styrene, p-amino-styrene,p-amino-benzyl-styrene, sodium styrene sulfonate, sodium2-sulfoxyethylmethacrylate, vinyl pyridine, aminoethyl methacrylates,and 2-methacryloyloxy-trimethylammonium chloride.
 4. A contrast mediumaccording to claim 1 wherein said microspheres comprise syntheticpolymers or copolymers selected from the group consisting of polyacrylicacid, polyethyleneimine, polymethacrylic acid, polymethylmethacrylate,polysiloxane, polydimethylsiloxane, polyactic acid,poly(ε-capro-lactone), epoxy resin, poly(ethylene oxide), poly(ethyleneglycol), polyamide, polyvinylidene-polyacrylonitrile,polyvinylidene-polyacrylonitrile-polymethylmethacrylate, andpolystyrene-polyacrylonitrile.
 5. A contrast medium according to claim 1wherein said microspheres comprise polyvinylidene-polyacrylonitrilecopolymer.
 6. A contrast medium according to claim 1 wherein themicrospheres are prepared by a heat expansion process.
 7. A contrastmedium according to claim 1 wherein said gas in said gas-filledmicrospheres is selected from the group consisting of carbon dioxide,oxygen, nitrogen, xenon, argon, neon and helium.